Folate is essential for normal cell growth and replication and is required for biochemical processes such as DNA and RNA synthesis and transmethylation reactions. The human alpha isoform folate receptor (FR-alpha; also known as folate receptor 1 (adult); FBP; FOLR; FOLR1; and MOv18) has a very high affinity for folic acid and is an essential component for cellular accumulation of folates and folate analogs used in the treatment of cancer.
Lacey et al. isolated a nearly full-length cDNA from a human carcinoma cell line library, and Elwood isolated human cDNA clones from human malignant nasopharyngeal carcinoma cell and placental cDNA libraries (Elwood, J Biol Chem, 1989, 264, 14893-14901; Lacey et al., J Clin Invest, 1989, 84, 715-720). Human FR-alpha levels have been found to be elevated in many cancer cell types. For example, the FR-alpha is highly overexpressed in some solid epithelial tumors such as ovarian carcinoma and mesothelioma. Other cancers with elevated levels include breast, brain, and colorectal cancers. FR-alpha has also been found to be a cofactor for cellular entry for Marburg and Ebola viruses (Chan et al., Cell, 2001, 106, 117-126).
Antisense technology is an effective means for reducing the expression of one or more specific gene products and is uniquely useful in a number of therapeutic, diagnostic, and research applications.
Disclosed herein are antisense compounds useful for modulating expression of FR-alpha via antisense mechanisms of action such as RNaseH, RNAi and dsRNA enzymes, as well as other antisense mechanisms based on target degradation or target occupancy. One having skill in the art, once armed with this disclosure will be able, without undue experimentation, to identify, prepare and exploit antisense compounds for these uses.